Centre for the AIDS Programme of Research in South Africa, KwaZulu-Natal Research Innovation and Sequencing Platform, School of Laboratory Medicine and Medical Sciences, Nelson R. Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
Genetics Department, Texas Biomedical Research Institute, San Antonio, TX, United States.
Front Immunol. 2018 Sep 7;9:2046. doi: 10.3389/fimmu.2018.02046. eCollection 2018.
The clinical outcomes of infections are highly variable among individuals and are determined by complex host-pathogen interactions. Genome-wide association studies (GWAS) are powerful tools to unravel common genetic variations that are associated with disease risk and clinical outcomes. However, GWAS has only rarely revealed information on the exact genetic elements and their effects underlying an association because the majority of the hits are within non-coding regions. Some of the variants or the linked polymorphisms are now being discovered to have functional significance, such as regulatory elements in the promoter and enhancer regions or the microRNA binding sites in the 3'untranslated region of the protein-coding genes, which influence transcription, RNA stability, and translation of the protein-coding genes. However, only 3% of the entire transcriptome is protein-coding, signifying that non-coding RNAs represent most of the transcripts. Thus, a large portion of previously identified intergenic GWAS single nucleotide polymorphisms (SNPs) is in the non-coding RNAs. The non-coding RNAs form a large-scale regulatory network across the transcriptome, greatly expanding the complexity of gene regulation. Accumulating evidence also suggests that the "non-coding" genome regions actively regulate the highly dynamic three dimensional (3D) chromatin structures, which are critical for genome function. Epigenetic modulation like DNA methylation and histone modifications further affect chromatin accessibility and gene expression adding another layer of complexity to the functional interpretation of genetic variation associated with disease outcomes. We provide an overview of the current information on the influence of variation in these "untranslated" regions of the human genome on infectious diseases. The focus of this review is infectious disease-associated polymorphisms and gene regulatory mechanisms of pathophysiological relevance.
个体之间感染的临床结果差异很大，这是由复杂的宿主-病原体相互作用决定的。全基因组关联研究（GWAS）是一种强大的工具，可以揭示与疾病风险和临床结果相关的常见遗传变异。然而，GWAS 很少能揭示与关联相关的的确切遗传因素及其影响，因为大多数命中都在非编码区域内。现在，一些变体或相关的多态性被发现具有功能意义，例如启动子和增强子区域中的调节元件，或蛋白质编码基因 3'非翻译区中的 microRNA 结合位点，它们影响转录、RNA 稳定性和蛋白质编码基因的翻译。然而，整个转录组中只有 3%是蛋白质编码基因，这意味着非编码 RNA 代表了大部分转录本。因此，以前确定的基因间 GWAS 单核苷酸多态性（SNP）的很大一部分位于非编码 RNA 中。非编码 RNA 在整个转录组中形成了一个大规模的调控网络，极大地增加了基因调控的复杂性。越来越多的证据还表明，“非编码”基因组区域积极调节高度动态的三维（3D）染色质结构，这对基因组功能至关重要。表观遗传修饰，如 DNA 甲基化和组蛋白修饰，进一步影响染色质可及性和基因表达，为与疾病结果相关的遗传变异的功能解释增加了另一层复杂性。我们提供了关于这些“未翻译”人类基因组区域的变异对传染病影响的最新信息概述。本综述的重点是与传染病相关的多态性和与病理生理相关的基因调控机制。
